Development of novel medical countermeasures against radiation is of foremost importance in the context of growing risk of nuclear terrorism or radiation accident scenarios. Under these circumstances, the victims could receive moderate radiation doses that will significantly increase the risk of death due to radiation induced bone marrow (BM) injury. Particularly, if the dose of IR is greater than 3 Gy, IR can severely damage hematopoietic stem cells (HSCs) and impair their ability to self-renew, which could ultimately lead to BM failure and organism death. Since severe damage to HSCs is the primary life-threatening injury after exposure to a moderate or high dose of IR (3-10 Gy), protecting HSC self-renewal should be a main goal in the development of life saving anti-radiation therapies. Recent studies from our laboratory and others suggest that p38 0-activated protein kinase (p38) is a negative regulator of HSC self- renewal and its activation may mediate IR-induced HSC injury and BM suppression. Therefore, we plan to elucidate the cellular and molecular mechanisms by which p38 mediates IR-induced impairment of HSC self-renewal and to determine whether p38 can be molecularly targeted for intervention to reduce IR-induced BM injury and lethality after total body irradiation (TBI) in a mouse model. In addition, we will determine if p38 inhibition can be used to promote ex vivo HSC expansion because the data presented in our preliminary studies suggest that activation of p38 can negatively regulate HSC self- renewal proliferation during ex vivo HSC expansion. This would allow HSC transplantation to be a more viable approach for post IR rescue therapy. We anticipate that the research proposed in this application will offer fundamentally new approaches to develop novel mechanism-based therapeutic strategies to mitigate or treat IR-induced BM injury, which could significantly improve the survival and quality of the life of radiation accident or nuclear terrorism victims. Nuclear terrorist attack, an increasing threat in the United States, can cause significant casualties due to radiation-induced normal tissue damage, particularly damage to the bone marrow (BM) and hematopoietic stem cells (HSCs). The goal of this project is to investigate the role of a protein called p38 in mediating radiation-induced HSC injury and BM suppression, which will allow us to develop novel and mechanism- based therapies to reduce radiation-induced BM damage to save lives in a nuclear event and to increase long-term survival of the nuclear victims.